The sympathies of the body: functional organization and neuronal differentiation in the peripheral sympathetic nervous system

Abstract

During the last 30 years, our understanding of the development and diversification of postganglionic sympathetic neurons has dramatically increased. In parallel, the list of target structures has been critically extended from the cardiovascular system and selected glandular structures to metabolically relevant tissues such as white and brown adipose tissue, lymphoid tissues, bone, and bone marrow. A critical question now emerges for the integration of the diverse sympathetic neuron classes into neural circuits specific for these different target tissues to achieve the homeostatic regulation of the physiological ends affected.

Keywords: Adiposity; Bone marrow; Cholinergic; Heartrate; Hydromineral; Hypertension; Immune status; Noradrenergic; Skeletal health; Synaptic organizer; Thermogenesis; Transdifferentiation.

Fig. 1

Regulatory domains in homeostatic demands, employed neurotransmitter systems and target tissues innervated by sympathetic postganglionic efferents. The figure displays the sympathetic transmitter systems employed in different target tissues. blue, noradrenergic; red, cholinergic. The data have been obtained by immunehistological detection of tyrosine hydroxylase as key marker for noradrenergic sympathetic neurons and by pharmacological discrimination of noradrenergic versus cholinergic activator or inhibitor-mediated actions. In the case of rodent sweat glands, also immunohistochemistry for choline acetyltransferase and the vesicular acetylcholine transporter have been employed in combination with retrograde labeling. Abbreviations: aa, arteries and arterioles; BAT, brown adipose tissue; MSCN: marrow stem cell niche; OST: osteoblast/osteoclast; Pancr., Pancreatic; LT: lymphatic tissue; WAT: white adipose tissue

Fig. 2

Expression of growth factor receptors and synaptic organizers of the protocadherin gene family in mouse thoracic sympathetic neuron classes. Expression level for the genes encoding the indicated receptor and organizer genes at larger than 0 (grey), 2 (yellow), 4 (orange), 8 (red), or 16 (dark red) mRNA molecules per cell. Data are taken from Furlan et al. (2016). While all noradrenergic neuron subpopulations (NA 1–5) show strong TRKA expression, the cholinergic sympathetic neurons show abundant RET expression. However, RET transcripts are detected in all, also noradrenergic sympathetic neuron classes. This observation was also made by quantitative density analysis of NBT/BCIP signals obtained from in situ hybridization in mouse cervical and thoracic sympathetic ganglia (UE, unpublished). Transcripts for GFRa receptor subunits can be detected at relatively low levels. GFRa1 and GFRa4 transcripts are not or barely observed (not displayed). GFRa3 is detected at very low levels in NA 1–5 but not in ACH 1 and ACH 2. Only GFRa2 is observed in significant levels in the cholinergic neuron populations and at low levels in noradrenergic neurons. For protocadherin transcripts, several important aspects could be derived from the single cell RNA sequencing data published by Furlan et al. (2016). Compared to other cell adhesion and synaptic organizer molecules, the PCDH gene family members are expressed very selectively in the different classes of sympathetic neurons (Ernsberger et al. 2020). For PCDH17, significant transcript levels are detected only in cholinergic neurons, not in noradrenergic neurons. The expression levels for PCDH 7, 9, 10, and A5 make it possible to distinguish all sympathetic neuron classes observed in the study. The transcripts of selected genes of the family could be detected at similar levels compared to those for TRKA and GDNF-family ligand receptors